Pharmaceutical composition

Abstract

The present invention relates to a novel pharmaceutical composition having enhanced bioavailability through improved aqueous dissolution of poorly water soluble drugs, and to a method for preparing it. The invention more particularly relates to an oral pharmaceutical composition containing active ingredients of poor aqueous solubility, more specifically, antiparasitic and antipneumocystic drug Atovaquone alone or in combination with Proguanil.

What is claimed is: 
     
       1. An aqueous soluble oral solid pharmaceutical composition comprising:
 1) atovaquone, 2) a pharmaceutically acceptable salt of atovaquone, or 3) a combination of atovaquone or a pharmaceutically acceptable salt of atovaquone with a second pharmaceutical drug substance, as active ingredient(s), 
 wherein an aqueous dissolution of the atovaquone present in the composition is at least 20% in 5 minutes, 30% in 10 minutes, 40% in 15 minutes, 50% in 30 minutes and 75% in 45 minutes, as measured using the rotating blade method at 75 rpm in a dissolution medium constituted by water containing 2.5% by weight sodium lauryl sulfate. 
 
     
     
       2. The aqueous soluble oral solid pharmaceutical composition according to  claim 1 , comprising:
 (a) atovaquone or its combination with the second pharmaceutical drug substance as active ingredient(s); 
 (b) at least one hydrophilic polymer, and optionally one or more surfactants or hydrosoluble carrier(s); and 
 (c) one or more pharmaceutical excipients. 
 
     
     
       3. The aqueous soluble oral solid pharmaceutical composition according to  claim 2 , wherein the second pharmaceutical drug substance is proguanil or a pharmaceutically acceptable salt, a complex or a prodrug thereof. 
     
     
       4. The aqueous soluble oral solid pharmaceutical composition according to  claim 3 , wherein the active ingredient(s) is in a homogenous phase with a hydrophilic polymer(s), and
 wherein the homogenous phase optionally includes one or more surfactant(s), and 
 wherein the hydrophilic polymer(s) is present in an amount at least 10% by weight of the amount of the atovaquone or the combined amount of the atovaquone and the proguanil. 
 
     
     
       5. The aqueous soluble oral solid pharmaceutical composition according to  claim 4 , wherein the phase homogeneity is at least 75% as characterized and quantified by XRPD. 
     
     
       6. The aqueous soluble oral solid pharmaceutical composition according to  claim 2 , wherein the at least one hydrophilic polymer is selected from a group consisting of poly (vinyl pyrrolidone), poly (vinyl alcohol), poly (vinyl acetate), poly (vinyl caprolactum), poly (ethylene glycol), a copolymer and a graft copolymer thereof, preferably a copolymer of poly (vinyl pyrrolidone) and poly (vinyl acetate) or a graft copolymer or poly (vinyl caprolactum), poly (vinyl acetate) and poly (ethylene glycol). 
     
     
       7. The aqueous soluble oral solid pharmaceutical composition according to  claim 2 , wherein the one or more surfactants are amphoteric, non-ionic, cationic or anionic surfactant, selected from a group consisting of sodium lauryl sulfate, monoleate, monolaurate, monopalmitate, monostearate or another ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, hydrogenated polyoxyethylene fatty acid glycerides, pluronic surfactants, and a mixture thereof. 
     
     
       8. The aqueous soluble oral solid pharmaceutical composition according to  claim 3 , wherein the composition comprises atovaquone-proguanil or a pharmaceutically acceptable salts, solvates or prodrugs thereof as the active ingredient, a copolymer of poly (vinyl pyrrolidone) and poly (vinyl acetate) as hydrophilic polymer, one or more pluronic surfactants and optionally one or more inert pharmaceutical excipients. 
     
     
       9. A dosage form suitable for oral administration comprising a discrete dosage form or a non-discrete dosage form, comprising a therapeutically effective amount of the composition according to  claim 1 , wherein the discrete dosage form is selected from one of a bolus, a pill, a tablet, and a capsule, and wherein the non-discrete dosage form comprises a powder or a granule. 
     
     
       10. The dosage form according to  claim 9 , wherein the discrete dosage form is a tablet prepared by molding in an inert liquid diluents or by compressing into a suitable machine a therapeutically effective amount of the composition according to  claim 1  in the form of a powder or granules, the tablets optionally being coated. 
     
     
       11. The dosage form according to  claim 9 , wherein, the discrete dosage form is a capsule prepared by filling a therapeutically effective amount of the composition according to  claim 1  in the form of a powder or granules, the capsule optionally sealed. 
     
     
       12. The dosage form according to  claim 9 , wherein the non-discrete dosage form is in the form of a powder, granules or a paste comprising a therapeutically effective amount of the composition according to  claim 1 , optionally filled in a vial or sachet. 
     
     
       13. A method of at least one of treatment and prophylaxis of a protozoal parasitic infection or an infection caused by  Pneumocystis  ( carinii )  jirovecii  in mammals, comprising the steps of administering the composition of  claim 1 . 
     
     
       14. The method of  claim 13 , wherein the protozoal parasitic infection is malaria, babesia, cryptosporidiosis, coccidiosis or toxoplasmosis. 
     
     
       15. The aqueous soluble oral solid pharmaceutical composition according to  claim 3 , wherein the phase homogeneity is at least 80% as characterized and quantified by XRPD. 
     
     
       16. The aqueous soluble oral solid pharmaceutical composition according to  claim 3 , wherein the phase homogeneity is at least 90% as characterized and quantified by XRPD. 
     
     
       17. The aqueous soluble oral solid pharmaceutical composition according to  claim 3 , wherein the phase homogeneity is 100% as characterized and quantified by XRPD. 
     
     
       18. The aqueous soluble oral solid pharmaceutical composition according to  claim 7 , wherein the pluronic surfactants is poloxamer, and wherein the poloxamer comprises compounds having different molecular weights. 
     
     
       19. The aqueous soluble oral solid pharmaceutical composition according to  claim 8 , wherein the copolymer of poly (vinyl pyrrolidone) and poly (vinyl acetate) is selected from one of copovidone or kollidon, wherein the one or more pluronic surfactants is polaxamer comprising compounds of different molecular weights, and wherein the optional one or more inert pharmaceutical excipients is selected from one of corn starch, microcrystalline cellulose, crospovidone, or lactose, or a mixture thereof.